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The present study was designed to check the serum levels of protease‐activated receptor (PAR‐1) in patients during different phases of dengue severity. Moreover, a correlation between serum PAR‐1 levels and hematological parameters, inflammatory cytokine levels, and liver functional changes was also determined. Based on the World Health Organization criteria, the study population was divided into: nonsevere dengue fever (DF; n = 30), severe dengue hemorrhagic fever (DHF; n = 19), and severe dengue shock syndrome (DSS; n = 11). The platelet count (PLT) and hematocrit (HCT) were analyzed using an automated hematology analyzer and liver function enzymes aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphate (ALP), bilirubin were checked by auto‐analyzer using diagnostic kits. Moreover, the levels of inflammatory mediators C‐reactive protein (CRP), tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐17 (IL‐17), and PAR‐1 were determined using respective ELISA kits. The HCT levels were elevated and platelet count decreased significantly during dengue complications (DHF and DSS) compared to the DF patients, while the levels of liver functional biomarkers AST, ALT, ALP, and bilirubin remained elevated in DHF and DSS groups than in the corresponding DF group. Similarly, the inflammatory cytokine levels of CRP, TNF‐α, IL‐6, and IL‐17 in DHF and DSS subjects were markedly increased when observed against DF subjects. Notably, the PAR‐1 levels were significantly elevated in DHF and DSS groups than in the DF group and positively correlated with changes in HCT levels, inflammatory biomarkers, and liver enzymes. Our findings conclude that PAR‐1 levels persistently increased with the severity of the dengue infection and are strongly associated with various clinical manifestations. Thus, PAR‐1 levels can be used as a diagnostic marker for assessing dengue severity. [ABSTRACT FROM AUTHOR]

Some evidence has demonstrated that both inflammation and immune cell dysregulation are coincident at late phase (post 24 h) of sepsis. The present study was designed to determine the pathological role of hyperinflammation and renal immune cells mobilization during late phase of sepsis induced acute kidney injury (S‐AKI) and tests the pharmacological effects of PDE‐4 inhibitor on these events. Sepsis was induced by cecal ligation puncture and renal function, oxidative–inflammatory stress biomarkers were assessed after 24 h. PDE‐4 inhibitor was administered for 7 days prior to induction of S‐AKI. Renal immune cells infiltration during sepsis was analyzed by H&E staining and papanicolaou staining method was used for detecting leukocytes and cast in urinary sediments, periodic acid schiff (PAS) staining was used for detection of brush border loss. AKI developed 24 h post sepsis insult as depicted by increase in serum creatinine, blood urea nitrogen (BUN), renal oxidative stress, and elevated inflammatory biomarkers levels. Moreover, septic rats displayed increased bacterial load, renal expression of phosphodiesterase‐4B, 4D isoforms, enhanced vascular permeability, caspase‐3 and myeloperoxidase activity, electrolyte imbalance, reduced Na+K+ATPase activity, declined cAMP levels, increased interstitial leukocyte infiltration, and leakage in urinary sediments along with histological alterations. Pre‐treatment with roflumilast at high dose completely prevented the various AKI associated manifestations in septic rats. Renal hyper‐inflammation and leukocyte infiltration was detected in late phase of S‐AKI. Roflumilast pre‐treatment resolved sepsis induced renal dysfunction and histological damage by suppressing late phase renal immune cells invasion and anti‐inflammatory effects mediated by up‐regulation of renal cAMP levels. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (I/R) injury is a common cause of acute kidney injury (AKI), which occurs clinically during renal organ transplantation and major cardiac surgeries. Previously, it was demonstrated that angiotensin II type 1 receptor (AT 1) receptor antagonism is beneficial in the resolution of AKI episodes in young rats by reducing inflammation and oxidative stress. However, studies have shown that aged kidneys are refractory to surgical ischemic pre-conditioning due to increased oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. Therefore, the present study was designed to evaluate the effects of pharmacologically induced pre-conditioning on I/R induced AKI in aged kidneys. AKI was induced by clamping both renal pedicels for 45 min followed by 24 h of reperfusion. The AT 1 receptor antagonist, losartan was administered for three days prior to I/R injury induction in both aged and young rats. Renal outcomes were assessed by serum creatinine, creatinine clearance and proteinuria, renal antioxidant enzyme assays, membrane Na+K+ATPase activity, inflammatory biomarkers, and histological studies. AKI developed 24 h post ischemia, as indicated by elevated serum creatinine levels, proteinuria, oxidative stress, reduced membrane Na+K+ATPase activity, increased inflammatory biomarkers levels and histological damage including cellular infiltration, tubular thickening, tubular dilation and necrosis. Losartan pre-treatment significantly improved renal dysfunction and histological alterations in young rats subjected to I/R injury. However, this treatment did not prevent various AKI manifestations in aged rats due to elevated oxidative and inflammatory stress mediated via tubular dysfunction and damage. We conclude that AT 1 receptor antagonism is not beneficial against renal I/R induced AKI in aged rats. • Renal ischemia-reperfusion (I/R) injury induced acute kidney injury in young and aged rats. • Acute tubular damage and coagulative necrosis score, tubular dysfunction was higher in aged sham and losartan pre-treated aged group. • Pre-treatment with Angiotensin type 1 receptor antagonist does not prevent AKI in aged ischemic rats due to elevated renal oxidative and inflammatory stress. [ABSTRACT FROM AUTHOR]

The up-regulation of Wnt/β-catenin pathway induces cardiac function abnormalities, hypertrophy, and fibrosis in diabetic hypertensive and pressure overload models. The present study investigates the cardioprotective effects of Wnt/β-catenin inhibition on isoproterenol (ISO) induced cardiotoxicity in rats. ISO was administered at a dose of 85 mg/kg (s.c) for 2 days. Wnt/β-catenin inhibitor pyrvinium (60 μg/kg, p.o) was given 2h prior and glibenclamide at a dose of 5 mg/kg; p.o, 2 h after ISO injection. Cardiac function parameters were assessed on isolated hearts by using automated Biopac apparatus. The β-catenin transcription and expression was detected by RT-PCR technique and immunohistochemical method. Serum and cardiac tissue biochemical changes including cardiac troponin-I, CK-MB, LDH, anti-oxidant enzyme levels, inflammatory cytokines, and membrane associated Na+/K + ATPase and Ca2+ATPase and caspase-3 activity, collagen content, fibronectin protein levels were evaluated in various study groups. Histological studies were also carried out to analyze the cardiomyocyte damage, hypertrophy, fibrosis, and necrosis, while α-SMA, TGF-β expression was checked by immunostaining. ISO administration enhanced β-catenin gene expression and transcription which promoted oxidative and nitrosative stress, inflammatory cytokine release, reduced ATP levels, induced over-expression of fibrotic proteins resulting in cardiac hypertrophy, myocardial necrosis, functional and histological changes. However, antagonism of Wnt/β-catenin pathway attenuated these ISO induced pathological manifestations. Notably, the co-treatment with ATP-sensitive K+ channel inhibitor partially, reduced the cardioprotective effects of Wnt/β-catenin blocker pyrvinium in ISO rats. Thus Wnt/β-catenin inhibition exhibits cardioprotective in ISO model by anti-oxidant, anti-inflammatory, anti-fibrotic properties and by possible involvement of ATP-sensitive potassium channel activation. [Display omitted] • High dose isoproterenol (ISO) induced cardiac oxidative stress, inflammation and necrosis. • Up-regulation of cardiac β-catenin expression and TGF-β, α-SMA was noted in ISO injected rats. • Wnt/β-catenin inhibitor pyrvinium abolished ISO induced cardiac pathological changes. • Cardioprotective effects of pyrvinium were partly reduced in K+-ATP channel inhibitor glibenclamide co-treated group. [ABSTRACT FROM AUTHOR]

Renal injury might originate from multiple factors like ischemia reperfusion (I/R), drug toxicity, cystic fibrosis, radio contrast agent etc. The four adenosine receptor subtypes have been identified and found to show diverse physiological and pathological roles in kidney diseases. The activation of A 1 adenosine receptor (A 1) protects against acute kidney injury by improving renal hemodynamic alterations, decreasing tubular necrosis and its inhibition might facilitate removal of toxin or drug metabolite in chronic kidney disease models. Furthermore, recent findings revealed that A 2A receptor subtype activation regulates macrophage phenotype in experimental models of nephritis. Interestingly the emerging role of adenosine kinase inhibitors in kidney diseases has been discussed which act by increasing adenosine availability at target sites and thereby promote A 2A receptor stimulation. In addition, the least explored adenosine receptor subtype A 3 inhibition was observed to exert anti- oxidant, immunosuppressive and anti-fibrotic effects, but more studies are required to confirm its benefits in other renal injury models. The clinical studies targeting A 1 receptor in patients with pre-existing kidney disease have yielded disappointing results, perhaps owing to the origin of unexpected neurological complications during the course of trial. Importantly, conducting well designed clinical trials and testing adenosine modulators with lesser brain penetrability could clear the way for clinical approval of these agents for patients with renal functional impairments. Unlabelled Image [ABSTRACT FROM AUTHOR]